CAP37 (cationic antimicrobial protein of Mr 37 kDa) was originally identified as a component of the oxygen-independent killing mechanism of the human neutrophil (PMN) and was demonstrated to have strong bactericidal activity for Gram negative organisms including Salmonella typhimurium, Escherichia coli, and Pseudomonas aeruginosa (Shafer et al., 1984; Shafer et al., 1986; Spitznagel 1990). Distinct from its effect on bacteria the native CAP37 protein has potent regulatory effects on host cells. It is an effective regulator of cells of the mononuclear phagocytic system such as monocytes (Pereira et al., 1990), microglia (Pereira et al., 2002) and macrophages (Larrick et al., 1991). It also regulates corneal epithelial (Ruan et al., 2002), endothelial (Lee et al., 2002; Lee et al., 2003) and smooth muscle cell functions (Gonzalez et al., 2004).
Structure function analysis of CAP37 enabled us to delineate its antibacterial domain to a region corresponding to residues 20 through 44 of the native molecule (Pereira et al., 1993). A peptide comprising this 25 amino acid sequence (CAP37(20-44)nat) mimicked the antimicrobial activity of the native molecule (Pereira et al., 1993) and extended its range of activity to encompass Staphylococcus aureus and Enterococcus faecalis, two Gram positive organisms. The bactericidal activity of the peptide was pH dependent, with maximum activity obtained between pH 5.0 and 5.5. Replacement of the cysteine residues at positions 26 and 42 with serine residues (CAP37(20-44)ser26/42) resulted in an inactive compound (Pereira et al., 1993). In vivo experiments demonstrated the efficacy of CAP37(20-44)nat in attenuating the lethal effects of E. coli lipopolysaccharide (LPS) in a conscious rat model of endotoxic shock (Bracket et al., 1997).
Infections due to the various Candida species can result in disease manifestations ranging from self limiting superficial infections to life threatening systemic infections (Nola et al., 2003). In the recent past there has been a dramatic increase in invasive fungal infections and Candida species are beginning to contribute substantially to serious hospital acquired infections (Clark and Hajjeh, 2002; Hobson 2003, Nola et al., 2003; Rapp 2004). The reasons for this are complex but can be attributed in major part to the latest advances in medicine leading to the increased survival of immunocompromised persons and the use of indwelling medical devices and catheters for treatment of hospitalized patients (Clark and Hajjeh 2002; Nola et al., 2003). The developing incidence of resistance to available anti-fungal drugs further compounds the clinical and public health problems associated with mycotic infections. New drugs having anti-fungal activity are needed. It is to this object that the present invention is directed.